Location bias contributes to functionally selective responses of biased CXCR3 agonists.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
04 10 2022
04 10 2022
Historique:
received:
28
01
2022
accepted:
13
09
2022
entrez:
4
10
2022
pubmed:
5
10
2022
medline:
7
10
2022
Statut:
epublish
Résumé
Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially activate specific signaling transducers over others. Although GPCRs are primarily found at the plasma membrane, GPCRs can traffic to and signal from many subcellular compartments. Here, we determine that differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands of the GPCR CXC chemokine receptor 3 (CXCR3). The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific manner. Endosomal signaling is critical for biased activation of G proteins, β-arrestins, and extracellular-signal-regulated kinase (ERK). In CD8 + T cells, the chemokines promote unique transcriptional responses predicted to regulate inflammatory pathways. In a mouse model of contact hypersensitivity, β-arrestin-biased CXCR3-mediated inflammation is dependent on receptor internalization. Our work demonstrates that differential subcellular signaling is critical to the overall biased response observed at CXCR3, which has important implications for drugs targeting chemokine receptors and other GPCRs.
Identifiants
pubmed: 36195635
doi: 10.1038/s41467-022-33569-2
pii: 10.1038/s41467-022-33569-2
pmc: PMC9532441
doi:
Substances chimiques
Chemokines
0
Cxcr3 protein, mouse
0
Ligands
0
Receptors, CXCR3
0
Receptors, G-Protein-Coupled
0
beta-Arrestins
0
GTP-Binding Proteins
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
5846Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM122798
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR073858
Pays : United States
Organisme : NHLBI NIH HHS
ID : K08 HL114643
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM145449
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007171
Pays : United States
Informations de copyright
© 2022. The Author(s).
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